tbuckley/cabot-search huggingface dataset:
Abstract 5359: M6A regulated NNMT mediates resistance to platinum in ovarian cancer
Authors: Hao Huang, Guangyuan Zhao, Andres Felipe Valdivia, Horacio Cardenas, Yinu Wang, Daniela Daniela Matei
Journal: Cancer Research (2022)

Abstract Background: Ovarian cancer (OC) remains one of the deadliest malignancies. Development of resistance to platinum (Pt) is a major clinical problem and understanding its underpinnings will help find new approaches to overcome it. Fat mass and obesity associated protein (FTO) is a N6-methyladenosine (m6A) demethylase and plays an important role regulating how the messenger RNA is processed translating into functional proteins. We recently showed that m6A modifications induced by FTO play a suppressive role in tumorigenicity and survival of OC stem cells. Here we hypothesized that RNA modifications caused by FTO regulate the response of OC cells to Pt. Methods: To study the mechanisms related to FTO implicated in response to Pt; we used OC cells in which FTO was knocked down (KD) via shRNA or overexpressed (OE). Additionally, Pt-resistant (Pt-R) OC cells were obtained through repeated (3-4) exposures to Pt. Cell viability assay determined the IC50 (half maximal inhibitory concentration) to Pt. Pt response in vivo was assessed in FTO expressing vs. FTO KD xenografts. Induction of DNA damage was assessed by immunofluorescence (IF) for γ-H2AX. Apoptosis was evaluated by Annexin V staining in the IncuCyte system. To identify potential targets of FTO-mediated m6A modifications in Pt induced response, RNA-seq and MeRIP-seq were integrated. Results: FTO was significantly downregulated in Pt-R vs. sensitive OC cells. Forced expression of FTO increased sensitivity to Pt in vitro and in vivo, while FTO KD increased Pt resistance (p&amp;lt;0.05). A catalytic mutant FTO did not appreciably alter responsiveness to Pt. Increased γ-H2AX foci and increased apoptosis were observed after exposure to Pt in FTO OE vs. control cells. Through integrated RNA-seq and MeRIP-seq, we identified and validated several potential targets involved in response to Pt including IER5, IER5, ST3Gal, and the enzyme nicotinamide N-methyltransferase (NNMT). NNMT was upregulated and significantly hypomethylated in FTO OE cells and was downregulated in Pt resistant cells. Treatment with an NNMT inhibitor rescued the FTO induced sensitivity to Pt in OC cells demonstrating that its function is necessary in the response to Pt. Conclusions: We identified a new function of FTO-dependent m6A RNA modifications in regulating response to Pt through NNMT, a novel RNA methylated target. Activating FTO could improve response to Pt in OC. Citation Format: Hao Huang, Guangyuan Zhao, Andres Felipe Valdivia, Horacio Cardenas, Yinu Wang, Daniela Daniela Matei. M6A regulated NNMT mediates resistance to platinum in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5359.
Bispecific T‐cell engagers for treatment of multiple myeloma
Authors: Gayathri Ravi, Luciano J. Costa
Journal: American Journal of Hematology (2022)

Abstract Bispecific T cell engagers (TCE) derive from monoclonal antibodies and concomitantly engage a target on the surface of cancer cell and CD3 on the surface of T‐cells. TCEs promote T cell activation and lysis of tumor cells. Most TCEs in development for multiple myeloma (MM) target the B cell maturation antigen (BCMA) and differ among themselves in structure, pharmacokinetics, route and schedule of administration. CD3/BCMA TCEs produce response in ~60% of patients treated in phase 1 trials. TCEs are also in development targeting the G protein‐coupled receptor, class C group 5 member D (GPRC5D) and the Fc receptor homologue 5 (FcRH5). Main toxicities are cytokine release syndrome and cytopenias. Here we review the current development and future directions of TCEs in MM.
Abstract 1160: Multi-scale deep learning feature distributions distinguish invasive ductal and lobular breast cancer slides
Authors: Patience Mukashyaka, Ali Foroughi Pour, Jeffrey H. Chuang
Journal: Cancer Research (2022)

Abstract Advances in digital pathology have streamlined use of deep learning methodologies to connect morphology and phenotype in hematoxylin and eosin(H&amp;E) stained images. Whole slide images (WSIs) are gigantic, necessitating a tile-based analysis: a WSI is broken into smaller images called tiles, each tile is analyzed separately, and tile level information are then combined to get a slide level prediction. Context aware models integrating tiles of different sizes have been used to combine morphological features present at different scales, and attention-based pipelines have successfully been used to combine tile level information. Pipelines that combine attention-based and context aware learning are less studied. While both methodologies have shown utility when used individually, models that combine both tend to suffer from a large number of parameters to estimate, which frustrates reliable training. Here we show percentiles of deep learning features extracted at different scales serve as a crude multiscale attention mechanism. The proposed model separates TCGA-BRCA invasive ductal and lobular carcinoma FFPE WSIs (AUC=0.85±0.02), which improves upon the performance of the fully tile-based model of [1] (AUC=0.80 ±0.04). The proposed approach enjoys higher average AUC and lower standard deviation across multiple random train/test splits of data. Our results suggest percentile-based feature construction is an interesting alternative when reliable training of fully deep learning models is challenging. References: [1] Noorbakhsh, J., Farahmand, S., Foroughi pour, A. et al. Deep learning-based cross-classifications reveal conserved spatial behaviors within tumor histological images. Nat Commun 11, 6367 (2020). https://doi.org/10.1038/s41467-020-20030-5 Citation Format: Patience Mukashyaka, Ali Foroughi Pour, Jeffrey H. Chuang. Multi-scale deep learning feature distributions distinguish invasive ductal and lobular breast cancer slides [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1160.
Circulating biomarkers for management of cancer therapeutics-related cardiac dysfunction
Authors: Claire Tonry, Adam Russell-Hallinan, Claire McCune, Patrick Collier, Mark Harbinson, Lana Dixon, Chris J Watson
Journal: Cardiovascular Research (2022)

Abstract Cancer therapeutics-related cardiac dysfunction (CTRCD) has emerged as a major cause of morbidity and mortality in cancer survivors. Effective clinical management of CTRCD is impeded by a lack of sensitive diagnostic and prognostic strategies. Circulating molecular markers could potentially address this need as they are often indicative of cardiac stress before cardiac damage can be detected clinically. A growing understanding of the underlying physiological mechanisms for CTRCD has inspired research efforts to identify novel pathophysiologically relevant biomarkers that may also guide development of cardio-protective therapeutic approaches. The purpose of this review is to evaluate current circulating biomarkers of cardiac stress and their potential role in diagnosis and management of CTRCD. We also discuss some emerging avenues for CTRCD-focused biomarker investigations.
Abstract 5799: Landscape of <i>TSC1</i> and <i>TSC2</i> mutations in patients with advanced solid cancers
Authors: Gunsagar S. Gulati, William Cacheris, Ritika Dutta, Jordi Rodon Ahnert
Journal: Cancer Research (2022)

Abstract Tuberous sclerosis proteins 1 and 2 (TSC1 and TSC2) are tumor suppressor genes and inhibitors of the mammalian target of rapamycin (mTOR) pathway. Mutations in these genes are candidates for novel mTOR inhibitors, such as nanoparticle albumin-bound (nab)-sirolimus, which have already demonstrated clinical efficacy in isolated case studies of patients with mutations in the mTOR pathway. However, the incidence of TSC1 and TSC2 mutations in the US and its distribution across tumors has not yet been systematically reported. Moreover, existing models for calculating incidence of targetable mutations do not account for cross-eligibility for other clinically approved targets. Therefore, here, we describe the landscape of TSC1 and TSC2 mutations across 16 solid tumors from The Cancer Genome Atlas (TCGA; n = 9,808 patients) and AACR GENIE database (MSK: n = 14,340 patients, DFCI: n = 5,271 patients) and estimate the annual incidence of eligible patients using the Surveillance, Epidemiology, and End Results Program (SEER) database. We then refined these estimates by excluding patients eligible for immunotherapy (tumor mutational burden (TMB) &amp;gt; 10 mutations/Mb) and other targeted therapies (n = 23 FDA-approved drug-targetable mutations). We find that the combined US incidence of patients with truncations (e.g. frameshift, nonsense, splice-site) or deep copy number deletions in TSC1 and TSC2 is ~11,000 ± 1,000 (mean Spearman ρ across datasets: 0.92). About 40% of these patients have mutations in at least one of 23 other drug-targetable genes. TSC1 and TSC2 mutations were most frequent in bladder and hepatobiliary cancers, respectively, with the absolute prevalence of mutations being highest in bladder and non-small-cell lung cancer. Among the patients with TSC1 and TSC2 mutations with other targetable mutations, we identified the most common co-occurring targetable mutations with TSC1 and TSC2, suggesting that combination or sequential treatment with immunotherapy and BRAF and FGFR3 inhibitors are possible options for clinical trials. Finally, we show that the combined annual US incidence of patients with TSC1 and TSC2 mutations is on average (n = 3 clinical genomic cohorts) higher than 17 of 23 other common targetable mutations. Our approach is now being used to estimate the population size of other medically relevant mutations and identify associated genomic targets for improved clinical trial design. Citation Format: Gunsagar S. Gulati, William Cacheris, Ritika Dutta, Jordi Rodon Ahnert. Landscape of TSC1 and TSC2 mutations in patients with advanced solid cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5799.
Abstract 50: Multi-omics and immune cell profiling of metastatic uveal melanomas
Authors: Justin C. Moser, Yusra F. Shao, Joanne Xiu, Yasmine Baca, Takami Sato, Lauren A. Dalvin, Sourat Darabi, Michael Korn, Burton Eisenberg, Geoff Gibney, Evidio Domingo-Musibay, Gino In, Dave Hoon, Michael S. Gordon
Journal: Cancer Research (2022)

Abstract Background: Uveal melanoma (UM) is a rare tumor of the eye which is biologically distinct from cutaneous melanoma (CM) and carries a poor prognosis once metastatic. We aimed to examine a multi-omics profile of UM as compared to CM. Methods: A total of 277 UM and 1,297 CM metastatic or primary samples were analyzed using next-generation sequencing (NextSeq, 592 genes and WES, NovaSeq, &amp;gt;700 genes) and whole transcriptome sequencing (WTS; NovaSeq) (Caris Life Sciences). Tumor mutational burden (TMB) was measured by totaling somatic mutations per tumor (TMB-high cutoff &amp;gt;10 mutations per MB). Immune cell fraction was calculated by QuantiSeq. T- cell inflamed score was calculated using gene expression data. Pathway gene enrichment analysis using WTS data was performed using GSEA. Biostatistical significance was determined using chi-square/Fisher-Exact or Wilcoxon rank sum test and adjusted for multiple comparisons. Results: For all cases (primary and metastatic), UM compared to CM had a higher rate of GNAQ/11 (93.8% vs. 2.1% p≤0.001), SF3B1 (20.4% vs 3% p≤0.001), and BAP1 (52.9% vs. 1.5% p≤0.001) mutations. UM also had higher levels of MYC (7% vs 0.9% p≤0.001), NCOA2 (3.1% vs 0.1% p≤0.001), and RUNX1T1 genomic amplifications (2.3% vs 0.2% p≤0.001). Assessing only samples of liver metastases, UM was shown to have higher abundance of M2 macrophages (P≤0.0001) and less abundance of M1 macrophages(P≤0.0001), monocytes(P≤0.0001), CD4 T-cells(P≤0.0001), and regulatory T-cells (p = 0.0003) as compared to CM. GSEA comparison between liver metastases of UM and CM samples showed G2M checkpoint (NES score, 1.60 p≤0.0001) and E2F targets (NES score, 1.58 p=0.002) to be higher in metastatic CM. When comparing T-cell inflamed, intermediate, and non-inflamed tumors from any site, CM or UM, the average Z scores for both G2M and E2F were highest for inflamed and lowest for non-inflamed, P≤0.0001. A similar trend of higher Z score was seen for TMB high vs TMB low tumors, p≤0.0001. Conclusions: UM and CM are characterized by significantly different genomic and transcriptomic alterations, and cellular composition of TME. Further understanding of these characteristics may lead to better treatment strategies for metastatic UM. Citation Format: Justin C. Moser, Yusra F. Shao, Joanne Xiu, Yasmine Baca, Takami Sato, Lauren A. Dalvin, Sourat Darabi, Michael Korn, Burton Eisenberg, Geoff Gibney, Evidio Domingo-Musibay, Gino In, Dave Hoon, Michael S. Gordon. Multi-omics and immune cell profiling of metastatic uveal melanomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 50.
Abstract 3587: Racial disparity in COVID-19 severity after adjusting for chronic illnesses and sociodemographic factors
Authors: Xiao-Cheng Wu, Yong Yi, Lauren S. Maniscalco, Mei-Chin Hsieh, DeAnn Gruber, Lee Mendoza, Theresa Sokol, Eileen T. Mederos, Augusto Ochoa
Journal: Cancer Research (2022)

Abstract Background. Research has reported that African American (AA) cancer patients with COVID-19 had a higher hospitalization rate than their white counterparts. Because the severity of COVID-19 is partly related to existing chronic diseases, one of the speculations is that racial differences in COVID-19 severity are attributable to AA cancer patients having a higher prevalence of chronic illnesses. Our study aimed to assess the impact of existing chronic diseases on the racial differences in hospitalization and length of hospitalization in COVID-19 cancer patients in Louisiana. Methods. We linked cancer cases diagnosed in 2015-2019 from the Louisiana Tumor Registry (LTR) with the statewide COVID-19 data to identify COVID-19 patients who had been previously diagnosed with cancer. We also identified chronic illnesses (i.e., heart disease, peripheral vascular and cerebrovascular diseases, pulmonary disease, renal disease, liver disease, diabetes, and others) from 2012-2020 hospital discharge data and LTR data. Age and census tract level poverty were at the time of COVID-19 diagnosis. Bivariate and multivariable logistic regressions were used to exam the association of race with hospitalization after adjusting for socio-demographic and chronic illnesses. The multivariable Poisson model was used to assess the racial disparity in length (in days) of hospitalization. Results. Of 6,518 COVID-19 cancer patients, there were 30.8% AA, 68.4% whites, and 0.8% other races. AA, male, older, residing in high poverty, and patients with chronic illnesses were more likely (P&amp;lt;0.05) to be hospitalized. The odds of hospitalization was 87.2% higher among AA patients than white patients in bivariate analysis. After adjusting for age, gender, poverty, obesity, smoking status, and chronic illnesses, the odds of hospitalization was still higher for AA than white patients (OR=1.81;95% CI: 1.55-2.09). The length of hospital stay for AA was more (P&amp;lt;0.05) than whites After adjusting for the same covariates. Conclusion. Sociodemographic factors and chronic illnesses are associated with the severity of COVID-19 among cancer patients. However, AA COVID-19 cancer patients have significantly higher odds of hospitalization and longer hospital stays even when controlling these factors. More research is warranted to determine underlying factors of the observed racial disparities. Citation Format: Xiao-Cheng Wu, Yong Yi, Lauren S. Maniscalco, Mei-Chin Hsieh, DeAnn Gruber, Lee Mendoza, Theresa Sokol, Eileen T. Mederos, Augusto Ochoa. Racial disparity in COVID-19 severity after adjusting for chronic illnesses and sociodemographic factors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3587.
Abstract 5423: Translational PK/PD/efficacy modeling and efficacious human dose prediction for a first-in-class MUC1-EGFR (M1231) bispecific antibody drug conjugate
Authors: Anup Zutshi, Berend Neuteboom, Seema Kumar, Willem Sloot, Christine Knuehl, Julia Dotterweich, Jianguo Ma, Christiane Amendt, Karthik Venkatakrishnan, Taeshin Park, John Pappas, Kyoung-Ae Kim
Journal: Cancer Research (2022)

Abstract Introduction: M1231 is a first-in-class bispecific antibody drug conjugate (ADC) targeting mucin-1 (MUC1) and epidermal growth factor receptor (EGFR), that is conjugated with a novel hemiasterlin-related microtubule inhibitor payload. Following dose, M1231 binds to EGFR and co-binds to tumor-associated hypoglycosylated MUC1, internalizes into the tumor cell and traffics to lysosomes where the payload is enzymatically released to affect cell viability. Methods: A Multi-scale Systems Pharmacology model was developed to account for the ADC’s disposition and interactions with the underlying physiologic system, resulting in intracellular payload release in tumor cells to drive tumor growth inhibition (TGI). An in vitro model quantified ADC internalization and lysosomal trafficking in the MUC1 and EGFR-expressing cancer cell lines MDA-MB-468 and OVCAR-3. TGI was assessed in mice bearing MUC1-tumors from the squamous NSCLC patient-derived xenograft model, LUX003. Pharmacokinetics in cynomolgus monkeys was modeled using a Target Mediated Drug Disposition model and was allometrically scaled to humans. Data Summary: All preclinical modeling results were integrated and scaled to simulate plasma M1231 concentrations to predict the human dose and corresponding exposures. Tumor stasis was estimated to begin at a dose of 2.4 mg/kg every 3 weeks (Q3W) with a maximum tumor regression achieved at a dose of 4.3 mg/kg Q3W. Conclusions: The quantitative systems pharmacology model-based efficacious dose prediction range of 2.4 mg/kg to 4.3 mg/kg dosed Q3W informed the design of the ongoing M1231 first-in-human trial (NCT04695847). Citation Format: Anup Zutshi, Berend Neuteboom, Seema Kumar, Willem Sloot, Christine Knuehl, Julia Dotterweich, Jianguo Ma, Christiane Amendt, Karthik Venkatakrishnan, Taeshin Park, John Pappas, Kyoung-Ae Kim. Translational PK/PD/efficacy modeling and efficacious human dose prediction for a first-in-class MUC1-EGFR (M1231) bispecific antibody drug conjugate [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5423.
Abstract 829: p53 dimers elicit tumor suppressive activities through an altered metabolic program
Authors: Jovanka Gencel-Augusto, Xiaoping Su, Guillermina Lozano
Journal: Cancer Research (2022)

Abstract p53 is the most frequently mutated gene in human cancer. As a tetrameric transcription factor, mutation of the p53 Tetramerization Domain (TD) is a mechanism by which cancers abrogate wild-type (WT) p53 function. p53 TD mutations result in a protein that preferentially forms monomers or dimers. Although it is accepted that tetrameric p53 is required for full tumor suppressive activities, the physiological relevance of monomeric and dimeric states of p53 is not well understood. We have established the first in vivo models for hot-spot p53 TD mutants, p53R339P and p53A344D (murine), that result in monomeric and dimeric p53, respectively. These models closely resemble Li-Fraumeni Syndrome (LFS) patients with germline p53 TD alterations and will be used to characterize their physiological activities. p53R339P and p53A344D proteins failed to form tetramers. These mutants were deficient in their transactivation ability for canonical p53 target genes, and unable to induce apoptosis following IR. Both p53 TD mutant mice rescued the p53-dependent embryo lethality caused by genetic deletion of Mdm2, suggesting these are loss-of-function alleles. Monomeric p53 bearing mice succumbed mainly to thymic lymphomas (~60%), with a median survival similar to p53-/- mice (~130 days). Dimeric p53 bearing mice displayed lower incidence of thymic lymphomas (~25%) and longer survival (~180 days). Analyses of the transcriptomes elicited after DNA damage in normal thymus revealed that the p53 signaling pathway is dampened in dimeric p53 thymi. However, under basal conditions, p53 dimers upregulate a lipid metabolic program that is associated with PPAR activation. Further RNA sequencing of common metabolic tissues of the mouse (pancreas, liver, and intestine) revealed that they upregulate lipid-related metabolic programs in p53 dimer samples. This study describes, for the first time, the consequences of altering p53 tetramerization in vivo. Monomer and dimer forms of p53 do not retain most WT p53 features. p53 dimers may exert tumor suppression as seen by extended survival and tumor spectra shift. p53 dimer-specific activities on PPAR signaling and lipid metabolism may explain these phenotypes. These activities are possible therapeutic targets for LFS patients. Citation Format: Jovanka Gencel-Augusto, Xiaoping Su, Guillermina Lozano. p53 dimers elicit tumor suppressive activities through an altered metabolic program [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 829.